Nitric oxide (NO) plays an important role in normal and pathological cerebrovascular functioning, including regulation of cerebral blood flow, and maintenance of perfusion during ischemia in the core and penumbral areas. In mice with diabetes (db/db) or atherosclerosis (apoE ko ) there is diminished phosphorylation of eNOS at the critical S1179 site. The investigators have generated ki mice carrying phosphomimetic (S1179D) and unphophorylatable (S1179A) forms of eNOS, in control, db/db and apoE-ko mice. They aim to prove that modulation of the S1179 eNOS phosphorylation site can influence vascular function under normal and pathological circumstances, and that improved phosphorylation improves cv reactivity in vivo and outcome in stroke in animals with diabetes and stroke. PUBLIC HEALTH RELEVANCE: The investigators have a long history of studying how known cardiovascular risk factors such as high blood pressure, diabetes and hypercholesterolemia lead to increased risk for stroke (and MI). Although it is already known that risk factors are associated with diminished phosphorylation at the S1179 site, while "risk antagonists", such as statins, insulin etc. are associated with increased phophorylation, the investigators can tease out with their very clever models what is simply association and what is causative. This may well lead to the development of new treatment options directly addressing the links between metabolic diseases and (cerebro)vascular disease.